OVERVIEW: What every practitioner needs to know

Are you sure your patient has a Mitochondrial disease? What are the typical findings for this disease?

Multiorgan system involvement is the hallmark, although some mitochondrial disorders affect a single organ such as the eye in Leber hereditary optic neuropathy (LHON) (see below).

Mitochondrial disorders are clinically heterogeneous.

Result from dysfunction of the mitochondrial respiratory chain.

Caused by mutations of either nuclear or mitochondrial DNA (nDNA or mtDNA).

Neurological involvement (central and/or peripheral nervous system) is the most common manifestation and can be present initially or later in the disease course, although other organ systems can be present early or later.

The specific findings depend upon the type of mitochondrial disorder, heteroplasmy and genetic background, although many of the phenotypes overlap.

Many individuals display a cluster of clinical features that define a discrete clinical syndrome or condition.

Recently, a number of patients with KSS have been found additionally to have cerebral folate deficiency

Other symptoms

Bilateral hearing loss or deafness

Myopathy

Dysphagia

Diabetes mellitus

Dementia

Hypoparathyroidism

Pearson syndrome

Childhood onset sideroblastic anemia

Pancytopenia

Exocrine pancreatic failure

Other symptoms:

May have cardiomyopathy and be fatal

Renal tubular acidosis

Pyruvate Dehydrogenase complex (PDH)

There are 3 primary clinical presentations for PDH

In the neonatal period, infants present with symptoms of lactic acidosis and cerebral dysgenesis.

Another set of patients develop Leigh’s encephalopathy in the first 5 years of life, with developmental delay, seizures, ataxia, episodic weakness, basal ganglia and brainstem dysfunction, and progressive neuropathy.

Less commonly, patients are initially much less severely affected, with intermittent episodes of ataxia and a slow progression over years to Leigh’s encephalopathy.

Overview of Mitochondrial Diseases

The range of symptoms can be early death to less severe abnormalities of brain and other organs to those involving a single organ system or just muscle fatigue and exercise intolerance.

The definitive diagnosis of a mitochondrial disorder can be difficult to establish.

Diagnosis can be challenging because of the protean nature of clinical manifestations.

Identical phenotypes can result from different genotypes with gene mutations in a mitochondrial gene or a nuclear gene or from epigenetic effects.

Conversely, the same genotype can give rise to varying phenotypes.

The interplay between nuclear and mitochondrial genomes creates the wide variety of presentations of mitochondrial disease that makes diagnosis difficult.

There are novel genetic concepts in mitochondrial biology such as heteroplasmy, threshold, age dependency on oxidative phosphorylation, and somatic mutations that further complicate recognition and diagnosis.

The Electroretinogram (ERG) may be abnormal, including small amplitude waveforms, or could be normal. There may be predominantly cone dysfunction in some pedigrees and mainly rod dysfunction in others.

The ocular manifestations of NARP are extremely variable and range from a mild salt and pepper retinopathy to bull's eye maculopathy and classic retinitis pigmentosa with bone spicule formation.

Electromyography (EMG) and nerve conduction studies may demonstrate peripheral neuropathy (which may be a sensory or sensorimotor axonal polyneuropathy).

MELAS

Presents with sudden onset of strokes, usually precipitated by focal or generalized seizures.

Usually has its onset in childhood, but can present at any age.

Children may be asymptomatic prior to this event or have varying degrees of underlying developmental disabilities.

Although recovery from stroke-like episodes in MELAS is typically rapid and may be complete early in the disease course, once the first stroke-like episode occurs, a patient's neurologic status continues to deteriorate.

Recurrent strokes result in increasing disability, dementia, and early death.

Other inborn errors can mimic the encephalopathy and seizures seen in mitochondrial disorders; they will be diagnosed by specific patterns of abnormalities on plasma amino acids and /or

urine organic acids.

Mutations in the RANBP2 gene affecting a nuclear pore protein present a similar phenotype.

Isolated bilateral striatal necrosis due to glutaric aciduria may mimic as well as mutations in the SLC25A19 agene,

Other mimics include hypoxic ischemic encephalopathy, viral and bacterial infections of the infant.

The vascular territories of focal brain lesions and the prior medical history of patients with MELAS differ substantially from those of typical patients with stroke.

Mitochondrial disorders should be considered any time a progressive multi-system disorder is suspected and sometimes for isolated symptoms such as optical atrophy, sensori-neuro deafness, cardiomyopathy, pseudo-obstruction, neuropathy, myopathy, liver disease, early strokes, seizures.

LHON

Leber hereditary optic neuropathy may be missed in patients who develop the multiple sclerosis-like illness.

Other mtDNA complex I mutations cause optic atrophy in association with severe neurologic deficits including ataxia, dystonia, and encephalopathy. Patients have also been identified with mtDNA complex I mutations and clinical features of both LHON and MELAS (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes).

Other causes of bilateral visual failure must be excluded.

Other causes of sporadic and inherited optic neuropathies should also be distinguished from LHON, including deafness-dystonia-optic neuropathy (DDON).

mt DNA deletion syndromes such as KSS and CPEO may overlap with the following other neurological conditions:

What caused this disease to develop at this time?

The severity of the mutation or degree of heteroplasmy may influence timing of disease manifestations in mitochondrial disorders.

Illness or other stressor may cause disease to manifest or acutely worsen the clinical presentation.

Several genetic etiologies are contributory for early onset diseases in LS for example, including mutations in nuclear genes such as SURF-1 and the COX assembly genes, mtDNA complex V (maternally inherited Leigh syndrome) or pyruvate dehydrogenase.

A convincing clinical history, physical examination, magnetic resonance imaging (MRI) pattern (see details below and Table 1), and family history may enable one to proceed with more definitive diagnosis. Lactate need not be elevated or may be elevated after certain conditions such as exercise, glucose loading, illness, or be elevated in the brain (CSF) only.

LHON typically presents in young adults.

95% of those who develop vision loss do so by 50 years of age.

In PDH, mutations of one of the subunits of the pyruvate dehydrogenase complex lead to dysfunction of the citric acid (Krebs) cycle. The body is deprived of energy derived from carbohydrate metabolism, and lactic acid accumulates.

In PDH, the disease process may begin in utero with cerebral dysgenesis or may manifest later in infancy or childhood.

In Barth syndrome, tafazzin, a phospholipid acyltransferase, is involved in acyl-specific remodeling of cardiolipin, which promotes structural uniformity and molecular symmetry among the cardiolipin molecular species. Inhibition of this pathway subsequently leads to changes in mitochondrial architecture and function which may be exacerbated by stress/developmental demand.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Several disorders have a distinct clinical or MRI presentation, such that one may go directly to molecular genetic testing (i.e. KS, MELAS, KSS, LHON).

Biochemical laboratory testing

Lactate is usually elevated in blood, but this is not a universal factor and can be normal at baseline. It is more likely to be elevated in the post-prandial state. Testing multiple blood samples is more sensitive than testing a single random sample, since lactate determination may be affected by several artifacts of collection, including tight tourniquet, patient crying or breath holding, or failure to transport on ice.

Lactate elevation is more consistent in CSF samples than blood samples but will require CSF collection by lumbar puncture or access to 1H MRS, which can noninvasively measure CNS lactate.

Plasma amino acids may show elevated alanine concentration (formed from the transamination of pyruvate), reflecting persistent elevation of plasma lactate concentration, but not in all cases.

Low plasma citrulline concentration has been reported in individuals with the m.8993T>G mutation.

Urine organic acid analysis often detects lactic aciduria (if present, is about 4 uM) and is useful in excluding other organic acidurias.

Biochemical results can be normal even in patients who are later proven to have a mitochondrial disorder. This is the case in individuals with mtDNA mutations affecting complex V subunits.

m.8993T>C mutations do not appear to show any significant variation in mutation load among tissues.

MELAS

80% of patients have an adenine to guanine transition at the tRNA for leucine at position 3243 in the mtDNA.

Mutations in MT-TL1 or MT-ND5.

Mutations can usually be detected in mtDNA from leukocytes.

Heteroplasmy can result in varying tissue distribution of mutated mtDNA.

Mutation may be undetectable in leukocytes and may be detected only in other tissues (cultured skin fibroblasts, hair follicles, urinary sediment, and skeletal muscle).

MERRF

(mtDNA) gene MT-TK encoding tRNALys is the gene most commonly associated with MERRF.

Over 80% have an A-to-G transition at nucleotide 8344 (m.8344A>G).

POLG-1

Identification of two disease-causing POLG mutations for all phenotypes except adPEO, for which identification of one disease-causing POLG mutation is diagnostic. POLG molecular genetic testing is available on a clinical basis.

Approximately 90% of individuals with KSS have a large-scale (i.e., 1.1- to 10-kb) mtDNA deletion that is usually present in all tissues but usually undetectable in blood therefore requiring examination of muscle.

In Pearson syndrome, mtDNA deletions are usually more abundant in blood than in other tissues.

In CPEO, mtDNA deletions are confined to skeletal muscle.

PDH

Sequence analysis of two of the genes associated with PDH are commercially available.

Involvement of the subcortical U fibers with sparing of the periventricular white matter differentiates it from most lysosomal and peroxisomal disorders where subcortical regions are only affected late in the disease.

Imaging in PDH:

Imaging studies may document cerebral dysgenesis in PDH.

Ventriculomegaly.

Cerebral atrophy.

Partial or complete absence of the corpus callosum.

Absence of the medullary pyramids, or dysmorphic or ectopic inferior olives.

Gliosis may be observed in the cortex, basal ganglia, brainstem, or cerebellum.

Diffuse hypomyelination.

Imaging in MNGIE:

Asymptomatic leukoencephalopathy.

Prominent leukoencephalopathy in almost all patients.

Corpus callosum is usually spared.

Confirming the diagnosis

Several paradigms have been developed to address the probability of having a mitochondrial disorder including the one from Baylor College of Medicine and the Walker and Bernier criteria:

PUBMED:12427892

http://www.bcm.edu/geneticlabs/index.cfm?pmid=15857 (algorithm)

If you are able to confirm that the patient has a mitochondrial disease, what treatment should be initiated?

Seizures: Appropriate antiepileptic drugs tailored to the type of seizure under the supervision of a neurologist. Sodium valproate and barbiturates should be avoided because of their inhibitory effects on the mitochondrial respiratory chain, especially in patients suspected or confirmed to have POLG-1 (see below).

Testing for POLG-1 is often advocated before even considering use of Valproate.

Dystonia: multiple drugs including, baclofen, tetrabenezine, and gabapentin may be useful, alone or in various combinations.

Botulinum toxin injection has also been used in individuals with spasticity or intractable dystonia.

Cardiomyopathy: Therapy for congestive heart failure may be required and should be supervised by a cardiologist.

All patients will benefit from regular assessment of daily caloric intake and adequacy of dietary structure including micronutrients.

Feeding management is indicated as many patients will require G tubes to meet caloric needs.

Some physicians will treat with a vitamin cocktail, but this is decided on an individual basis (see also below).

MELAS : there is some evidence that arginine and/or citrulline may prevent further strokes by action on neuronal NOS influencing vascular tone.

In 2006, Koga, et al. noted that patients with MELAS had significantly low levels of L-arginine during the acute phase of their stroke-like episodes and showed effectiveness of arginine in decreasing the severity of stroke-like symptoms, reducing the frequency of stroke-like episodes, enhancing circulatory dynamics, and reducing tissue injury although there have been no official clinical trials.

Management of visual loss in LHON is supportive and includes visual aids and registration with social services if a patient meets criteria for legal blindness.

Mitochondrial disorders with secondary cerebral folate deficiency may be treated with folinic acid.

Some physicians will treat with a vitamin cocktail containing coenzyme Q10, carnitor, thiamine, riboflavin, lipoic acid, vitamin C, vitamin E, possibly creatinine, however there is not consensus on this or what elements to add to the cocktail.

Dichloroacetate is toxic to peripheral nerves, particularly in MELAS; it may be helpful in Leigh syndrome and PDH.

EPI 743.

Ubiquinone.

Magnesium has been used recently to treat the refractory seizures associated with POLG1.

Barth syndrome: One trial with pantothenic acid failed to reduce the number of infectious episodes and prevent dilated cardiomyopathy. Surveillance for infection and cardiomyopathy constitute treatment. Management of developmental issues with appropriate therapies is recommended.

There are studies underway using EPI-743, an antioxidant in Leigh syndrome and other mitochondrial disorders.

MNGIE

Management of GI dysfunction and nausea and vomiting, early attention to swallowing difficulties.

Celiac plexus block with bupivicaine for GI pain in MNGIE. Splanchnic nerve block has been used.

May include riboflavin, thiamine, and coenzyme Q10 (each at 50-100 mg/3x/day).

A high-fat diet, providing 50-60% of daily caloric intake from fat, may be prescribed to individuals with Leigh syndrome resulting from complex I deficiency, although currently there is no evidence supporting this therapeutic rationale in this particular disorder.

Biotin, creatine, succinate, and idebenone have also been used and may show partial efficacy in patients who have milder symptoms.

Several recent studies have investigated whether upregulation of mitochondrial biogenesis may provide an effective therapeutic approach for mitochondrial respiratory chain diseases using agonists such as bezafibrate or resveratrol which stimulate the peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator alpha (PGC-1alpha) path.

What are the adverse effects associated with each treatment option?

Arginine at high levels can cause peripheral nerve damage.

Dichloroacetate can lead to hepatic failure and peripheral neuropathy.

Sodium valproate and barbiturates, and anesthesia, worsen mitochondrial function and should be avoided because of their inhibitory effect on the mitochondrial respiratory chain.

Ketogenic diet may worsen pyruvate carboxylase.

What are the possible outcomes of Mitochondrial diseases?

The prognosis of LS is poor, especially in infancy-onset disease, as most children will die in the first years of life.

Mitochondrial disorders are generally progressive, although there may be decompensation with some recovery; however, the net effect is a decline over time.

Most children die of an intercurrent infection, which compromises their pulmonary function.

MELAS may stabilize, or present with recurrent strokes over time with resultant loss of previous motor and cognitive function, resulting in fixed motor deficits and dementia.

Mitochondrial dysfunction is also involved in normal aging and age-related neurodegenerative diseases such as Parkinson and Alzheimer dementia.

About 20% of mitochondrial diseases are inherited maternally, as little or no mtDNA is transferred from sperm to the fertilized egg.

Mitochondrial diseases can also occur sporadically or be inherited in an autosomal dominant or recessive manner.

More than 200 mitochondrial DNA (mtDNA) point mutations or deletions have been associated with mitochondrial disease.

Approximately 100 nuclear DNA (nDNA) mutations have also been described, mostly since 2006.

Disease can occur across the lifespan, since the regulation of many mitochondrial proteins is developmental and may also be impacted by environmental toxins.

Carrier proteins normally acting as chaperonins and mitochondrial fusion/fission abnormalities have also been described as the causes for mitochondrial diseases.

There can be tissue specific mtDNA changes that are hard to detect with only non-invasive blood or urine studies.

Clinical presentation of some mitochondrial disorders such as LHON (Leber’s Heritary Optic Neuropathy) and sensori-neuro deafness may be impacted by gene-gene interactions.

Primary LHON-causing mtDNA mutations have reduced penetrance - 50% of males and 90% of females with a known mutation do not develop blindness.

Gender (males are on average four times more likely to develop vision loss) and age (blindness is unlikely to develop if not present by 50 years of age) are important risk factors.

History, including family history with evidence of a maternal inheritance pattern characteristic of mitochondrial disease.

How do these pathogens/genes/exposures cause the disease?

The genes involved in mitochondrial disorders play a role in the function of the mitochondrial respiratory chain.

Most patients with mitochondrial disorders have molecular defects affecting the mitochondrial OXPHOS system, which is made up of 87 protein subunits forming five multiprotein complexes (Complexes I–V) embedded in the inner mitochondrial membrane.

Among the 87 proteins, 13 are encoded by the mitochondrial genome and the remainder are encoded by the nuclear genome.

To form the OXPHOS complexes, a number of nuclear-encoded assembly factors are required.

Certain mutations of the pyruvate dehyrogenase complex influence the timing of presentation of disease features.

Patients with a PDH mutation are more susceptible to malnutrition as well as infection and other periods of increased energy demands.

Other clinical manifestations that might help with diagnosis and management

In addition to findings suggestive of lactic acidosis, particular features on physical exam may support the diagnosis of PDH. There is a characteristic dysmorphology that includes trigonocephaly, hypertelorism, a thin upper lip, bilateral epicanthal folds, upward slanting eyes, high palate, and pectus excavatum.

(This manuscript describes the criteria that are most likely to diagnose a patient with a mitochondrial disorder using a combination of clinical, biochemical, imaging, molecular and pathology findings. It is a modification of the Walker criteria [see below] which was felt to rely on features more common in adult rather than pediatric mitochondrial disorders.)PUBMED:18055683

(This manuscript presents another attempt in reaching consensus in diagnosis of young children and infants.)

Ongoing controversies regarding etiology, diagnosis, treatment

The diagnosis of mitochondrial disorders is often not straightforward and takes into account clinical history, physical examination features, family history, biochemical and other laboratory findings, imaging findings and is confirmed by a molecular finding. Some clinicians advocate muscle biopsy whereas others focus on findings from the laboratories and promote early molecular testing.

While there are guidelines, there is no consensus on diagnosis and treatment which is still empiric.